This is a revision for Risk Factors and the Neurobiologic Substrate of Frailty (R01AG024480) which was originally funded in July, 2005. The goal of the original application was two-fold: 1) to link risk factors (quantitative measures of physical activity using actigraphy and serum IGF-1 to change in frailty over time in order to establish the temporal relation between both risk factors and the development of frailty, and 2) to examine the relation of risk factors to post-mortem measures of spinal motor neuron counts and muscle dennervation and to clinical measures of frailty proximate to death in order to investigate biologic pathways linking risk factors to frailty. The Frailty Study has been rebudgeted under a NIA approved contingency plan to maintain essential operational activities previously provided by the parent study whose funding ended August 31, 2006. Under this plan, essential clinical measures, serum, spinal cord and muscle continue to be collected and stored but laboratory analyses of serum and histopathologic studies of spinal cord and muscle are contingent on obtaining funding from another source. We have enrolled 980 participants with clinical measures and serum on about 90% and obtained spinal cords on 85% of the 81 participants who have died. Impaired motor function is a prominent characteristic of frailty, a heterogeneous syndrome whose features include loss of strength and muscle mass, impaired gait, and fatigue. We hypothesize that degenerative changes in spinal motor neurons and muscle contribute to the development of frailty in aging. We further hypothesize that, since physical activity and the growth factor IGF-I affect the integrity of spinal motor neurons, the association of physical activity and IGF-1 with frailty is mediated through degeneration of spinal motor neurons. Since most information concerning frailty comes from studies limited to clinical measures, a strong advantage of this proposed supplement is that it will allow us to integrate a quantitative post-mortem assessment of spinal motor neurons and muscle atrophy into a study of risk factors for clinical frailty. The availability of risk factor data prior to the onset of frailty, measures of frailty proximate to death, and spinal cord and muscle, offers the opportunity to greatly increase our understanding of how risk factors lead to the development of physical frailty. [unreadable] [unreadable] [unreadable]